Host Cell Targets in HCV Therapy: Novel Strategy or Proven Practice?

Abstract

The development of novel antiviral drugs against hepatitis C is a challenging and competitive area of research. Progress of this research has been hampered due to the quasispecies nature of the hepatitis C virus, the absence of cellular infection models and the lack of easily accessible and highly representative animal models. The current combination therapy consisting of interferon-alpha and ribavirin mainly acts by supporting host cell defence. These therapeutics are the prototypic representatives of indirect antiviral agents as they act on cellular targets. However, the therapy is not a cure, when considered from the long-term perspective, for almost half of the chronically infected patients. This draws attention to the urgent need for more efficient treatments. Novel anti-hepatitis C treatments under study are directed against a number of so-called direct antiviral targets such as polymerases and proteases, which are encoded by the virus. Although such direct antiviral approaches have proven to be successful in several viral indications, there is a risk of resistant viruses developing. In order to avoid resistance, the development of indirect antiviral compounds has to be intensified. These act on host cell targets either by boosting the immune response or by blocking the virus host cell interaction. A particularly interesting approach is the development of inhibitors that interfere with signal transduction, such as protein kinase inhibitors. The purpose of this review is to stress the importance of developing indirect antiviral agents that act on host cell targets. In doing so, a large source of potential targets and mechanisms can be exploited, thus increasing the likelihood of success. Ultimately, combination therapies consisting of drugs against direct and indirect viral targets will most probably provide the solution to fighting and eradicating hepatitis C virus in patients.

Expression of Gastrointestinal Glutathione Peroxidase Is Inversely Correlated to the Presence of Hepatitis C Virus Subgenomic RNA in Human Liver Cells

“…9). To overcome these limitations, a human hepatoma cell line (HuH7) was transfected with subgenomic HCV RNAs, called replicons ( Fig.…”

CDK9/Cyclin T1: A Host Cell Target for Antiretroviral Therapy

“…In contrast to clinical practice for hepatitis C-infected patients [7], the selection of host cell targets, which are leading to the generation of indirect antiviral drugs has no real history in HIV drug discovery. In the following sections, the authors summarize indirect anti-HIV targets, with a particular focus on CDK9.…”

“…• Currently, protein kinases are regarded as the largest drug target family of the human kinome and subject to extensive pharmaceutical interest [8][9][10] • As a consequence of point two, inhibition of protein kinases using small molecule inhibitors has turned into a general strategy in the field of targeted drug discovery [8] • Viruses encode many proteins that are substrates to host cell kinase phosphorylation such as the HIV proteins, Vpu and Rev (Table 1) • Viral proteins are not just substrates to host cell protein kinases, they also interfere with the activation and activity of kinases [7] The human serine/threonine protein kinase, cyclin-dependent kinase (CDK)9 is amongst those protein kinases that are hijacked by HIV (Table 1). In complex with the HIV protein Tat, CDK9/cyclin T1 is an essential factor of HIV replication.…”

“…Viruses in general and HIV in particular utilize the host cell's signal transduction machinery to facilitate their own replication and propagation. Drugs that modulate the host cell rather than the virus are termed indirect antiviral drugs [7]. Agents that interfere with the hijacked host cell's signaling cascades are unlikely to be subject to resistance formation, since a mutated virus still needs the host cell's equipment for its propagation.…”

A novel class of geldanamycin derivatives as HCV replication inhibitors targeting on Hsp90: synthesis, structure–activity relationships and anti-HCV activity in GS4.3 replicon cells

“…4 Recent research has shown that intracellular cofactors are the most promising targets for the design of specific drugs that reduce the resistance to virus. 7 Several viruses require viral and host molecular chaperones for entry, replication and assembly, as well as for other steps in viral production. 8,9 Recently, Hsp90 was found to be able to bind to human FKBP8 and form a complex with HCV NS5A.…”